The Problem of Failed Trials ó and One Piece of the Solution

By Robin Elliott

Over the past five years, more than a dozen potential treatments for Parkinson’s disease (PD) have gone through clinical trials in the United States. All but two turned out negative.

This dismal count represents disappointments for everyone — the study volunteers who went to considerable trouble and some risk to participate, the companies that lost money, the doctors who invested their time … and the Parkinson’s community as a whole, which has waited patiently through what seems to have been the worst drought in the flow of new Parkinson’s treatments since the discovery of levodopa almost a half-century ago.

Why this sorry record? What can we — and you — do to improve it?

Over the summer, I put the question to more than a dozen of the most knowledgeable Parkinson’s scientists in the United States. I would like to share with our readers some of what I learned — and conclude with an idea for something we can do today to improve and accelerate the search for new therapies.

First, a couple of general observations. One is that the problem is not something unique to Parkinson’s. In other areas, one prominent scientist from the National Institutes of Health (NIH) told me much more money has been spent, with fewer results, than it has in Parkinson’s. The failure rate in all disease areas is a measure of the immense challenge that scientists face in identifying and tracking the mechanisms of diseases and then in translating these findings into the development of new treatments.

Second, a negative finding is not the same as a failure. When we do get within sight of tomorrow’s “cures,” we will likely find ourselves standing on the shoulders of yesterday’s “failures.” To pick a real-life example, the lessons we learned about the growth factor GDNF in a Phase II trial that failed in 2004 are being applied today in two new trials.

Six Obstacles to Research

So why does the treatment pipeline move so slowly? I list six reasons that were mentioned most often in these conversations.

We need to know more about the basic science of Parkinson’s. We have come a long way, but we still don’t understand enough about what causes the disease. Because of this, finding new drugs to treat it is a bit like looking for a needle in a haystack. Well, not quite; we do usually begin with a hypothesis about how something works before we send it on its way to a target in the brain. But the process would be much easier if we knew more about the origins and nature of the disease, and this will only happen if we fight in the political arena for adequate funding for basic medical research — especially what is done through the NIH, which is by far the largest funder of research at this stage.

Mice don’t get Parkinson’s. Nor, for that matter, do monkeys. Yet these are the organisms in which the tests are done before new drugs are tested in people. What this means is that just because something works in a mouse or a monkey doesn’t mean that it will work in a human.

We clearly need to find better animal models by supporting the work of scientists such as Ane Korff, Ph.D., of St. Jude Children’s Research Hospital, a recent PDF research fellow who is working on finding a new mouse model of Parkinson's.

Parkinson’s may not be just a single disease, but several. One implication of this is that a treatment that works for one group of people — for example, those who have specific genetic or clinical characteristics — may not for another. Yet most trials are done across large and complex populations — meaning that many partially successful trials are branded failures. We need to invest more in identifying these subtypes and in finding economical ways of developing treatments to address them.

My baby is the most beautiful in the world. Of course — but when this attitude is brought to a clinical study by someone who is passionately convinced that the treatment is going to work — be it a company, a study director, or even a study participant — it can lead to misplaced enthusiasm and the ignoring of negative signals early in the research process.

We need to perform more critical analysis of earlier data — especially in the pre-clinical (that is, animal) phase of the process. It was partly with this in mind that PDF chose to fund Daniel Segal, Ph.D., a neuroscientist at Tel Aviv University in Israel, to study whether a molecule that has shown promise in the lab has the potential to become a PD therapy.

Our statistical methods need work. According to Steven Piantadosi, M.D., a professor of mathematics at University of California, Los Angeles, the methods we use to measure the efficacy of investigational drugs in the early stages of the research process tend to exaggerate the promise of the treatments, and to give false optimism in the design of later-stage trials. He suggests that we take a harder look at animal studies and early human trials before proceeding to the later and more expensive stages.

We need more sensitive and accurate markers of how Parkinson’s progresses over time. The clinical observations of a doctor — even a very good one — are not sufficiently fine-grained to measure small changes in Parkinson’s progression with the accuracy or speed that are needed to perform trials efficiently. What we need is a brain-based version of the global positioning system (GPS) that is used in a car — something that will tell doctors, using imaging techniques or chemical analysis of blood or spinal fluid, where exactly a person is in his or her Parkinson’s “journey,” and that will enable them to tell whether an investigational drug is helping to slow or reverse the disease.

What Next?

These conversations drove home for me the scientific complexities of the problem and the difficulties in getting new Parkinson’s treatments discovered, developed and deployed. But they also suggested to me the need for creating an additional “front” in the drive for new therapies — one that channels constructively the collective voice of the people who have the greatest stake of all in the process: the people living with Parkinson’s and their families. I call this “the power of research advocacy.”

The Power of Research Advocacy

Research advocacy is an innovation that for years has been hiding in plain sight. It means formally integrating into the research process the unique knowledge, insight and urgency of people who live with Parkinson’s and their families.

Over the past decade, PDF — building on the visionary work of the Parkinson Pipeline Project, a group of people with Parkinson’s who have dedicated themselves to the cause of accelerating the development of new treatments — has taken the lead in Parkinson’s research advocacy. We have done this through such initiatives as creating a community-wide website listing clinical studies (www.PDtrials.org) and staging a series of roundtables to find solutions to obstacles in research.

These research advocates have the leadership skills to interact with the scientific community and influence research decision-making at all levels, and they are already having an impact — through the roles they play as research educators of support groups; advisors on study design; participants in institutional review boards; advocates in public policy matters; and community representatives and presenters at professional conferences held by groups such as the Parkinson Study Group and the Movement Disorder Society.

PDF itself now incorporates research advocates in every single aspect of the review process that we use for our scientific grants. We are always on the lookout for others who may want to work with PAIR and are preparing to add new research advocates to the team through the three regional institutes that we will be staging in 2011–12.

We believe that engaging people living with Parkinson’s disease in research decision-making is not just a warm and fuzzy idea; it is a vital means to improving the design, conduct and outcomes of clinical research down the road. It will create the opportunity to channel the energies of people with Parkinson’s as active participants at the core of the research enterprise. And it will provide a conscience, and a good source of authentic intelligence to the process that has a single goal: improving the lives of people who live with Parkinson’s disease.
Mr. Elliott is the Executive Director of the Parkinson's Disease Foundation.